Phosphoinositide-3-kinases (PI3Ks) are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into at least three classes (Classes I, II, and III) and play an important role in cellular signaling (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357). Class I enzymes are further classified into Classes Ia and Ib based on their mechanism of activation; Class Ia PI3Ks are heterodimeric structures consisting of a catalytic subunit (p110α, p110β, or p110δ) in complex with a regulatory p85 subunit, while the class-Ib PI3K (p110γ) is structurally similar but lacks the p85 regulatory subunit, and instead is activated by βγ subunits of heterotrimeric G-proteins (Walker et al., Mol. Cell. 2000, 6, 909). The human protein sequence of the p110α isoform is described in Volina et al., Genomics 1994, 24, 472; and Stirdivant et al., Bioorg. Med. Chem. 1997, 5, 65.
PI3Ks play a variety of roles in normal tissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with p110α having a specific role in cancer growth, p110β in thrombus formation mediated by integrin αIIβ3 (Jackson et al., Nat. Med. 2005, 11, 507), and p110γ in inflammation, rheumatoid arthritis (Camps et al., Nat. Med. 2005, 11, 936) and other chronic inflammation states (Barber et al., Nat. Med. 2005, 11, 933). The PI3K enzymes produce phosphoinositide 3,4,5-triphosphate (PIP3) from the corresponding diphosphate (PIP2), thus recruiting AKT (protein kinase B) through its Pleckstrin homology (PH) domain to the plasma membrane. Once bound, AKT is phosphorylated and activated by other membrane bound kinases and is central to a cascade of events that lead to inhibition of apoptosis (Berrie, Exp. Opin. Invest. Drugs 2001, 10, 1085).
The p110α isoform is selectively amplified and activated in a number of cancer types (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357; Stauffer et al., Curr. Med. Chem.—Anti-Cancer Agents 2005, 5, 449). In addition, there is a high frequency of non-random mutations in specific sites, primarily in the C2 domain and or the activation loop, of the kinase in several human cancer cell lines, including colon, brain, breast, and stomach (Samuels et al., Science 2004, 304, 554). This results in a constitutively active enzyme (Ikenoue et al., Cancer Res. 2005, 65, 4562; Kang et al., Proc. Natl. Acad. Sci. USA 2005, 102, 802), making p110α one of the most highly mutated oncogenes found in human tumors. Structural studies have shown that many of the mutations occur at residues lying at the interfaces between p110α and p85α or between the kinase domain of p110α and other domains within the catalytic subunit (Miled et al., Science 2007, 317, 239; Huang et al., Science 2007, 318, 1744).
While PI3K isoenzymes play important roles in many cellular processes, published experimental studies in mice with human tumor xenografts show that the pan-PI3K inhibitor LY294002 is well-tolerated, reduces signaling through the PI3K pathway, causes reduction of tumor volume, and is more active in cell lines over-expressing mutant forms of p110α than parental control cells (Semba et al., Clin. Cancer Res. 2002, 8, 1957; Hu et al., Cancer Res. 2002, 62, 1087).
Thus, PI3K, especially the p110α isoform, is an interesting target for drug intervention. Several classes of compounds have been identified as reversible inhibitors; for example, LY 294002 (non-selective) (Walker et al., Mol. Cell. 2000, 6, 909), PI103 (slightly α-selective) (Knight et al., Cell 2006, 125, 733; Hayakawa et al., Bioorg. Med. Chem. Lett. 2007, 17, 2438; Raynaud et al., Cancer Res. 2007, 67, 5840), ZSTK474 (non-selective) (Yaguchi et al., J. Natl. Cancer Inst. 2006, 98, 545; Kong et al., Cancer Sci. 2007, 98, 1639), TGX221 (β-selective) (Jackson et al., Nat. Med. 2005, 11, 507), oxazines (γ-selective) (Lanni et al., Bioorg. Med. Chem. Lett. 2007, 17, 756), IC87114 (δ-selective) (Sadhu et al. WO 2001/81346; Billottet et al., Oncogene 2006, 25, 6648), AS605240 (γ-selective) (Camps et al., Nat. Med. 2005, 11, 936), the imidazo[1,2-a]pyridines (α-selective) (Hayakawa et al., Bioorg. Med. Chem. 2007, 15, 403; Hayakawa et al., Bioorg. Med. Chem. 2007, 15, 5837), and the imidazo[4,5-c]quinoline NVP-BEZ235 (Garcia-Echeverria, et al., WO 2006/122806).

Despite the advances in developing PI3K inhibitors, there is a need for PI3K inhibitors for treatment of cancer.